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Topic

Reelin, Stress, and Inflammation: Implications for Treatment of Major Depression and Diagnosis of Alzheimer’s Disease”

Division of Medical Sciences

Date & location

• Friday, January 10, 2025
• 10:00 A.M.
• Medical Sciences Building, Room 150

Examining Committee

Supervisory Committee

• Dr. Hector Caruncho, Division of Medical Sciences, University of Victoria (Co-Supervisor)
• Dr. Lisa Kalynchuk, Division of Medical Sciences, UVic (Co-Supervisor)
• Dr. Marie-Eve Tremblay, Division of Medical Sciences, UVic (Member)
• Dr. Brianna Turner, Department of Psychology, UVic (Outside Member)

External Examiner

• Dr. Robert Laprairie, College of Pharmacy and Nutrition, University of Saskatchewan

Chair of Oral Examination

• Dr. Sandra Gibbons, School of Exercise Science, Physical and Health Education, UVic

Abstract

Reelin has been recognized for playing a role in various neuropsychiatric disorders including major depression and Alzheimer’s disease. It was demonstrated that Reelin signaling is implicated in various molecular pathways that are affected in these disorders, including but not limited to trafficking of AMPA receptors required for long-term potentiation and synaptic plasticity, regulation of amyloid beta and the phosphorylation of tau. Both major depression and Alzheimer’s are marked by reduced Reelin expression and alterations to Reelin cleavage. More recently, it has been shown that Reelin can be administered to animals exposed to chronic stress to relive depression-like behaviour and spatial memory deficits associated with chronic stress exposure.

While it has long been recognized that inflammatory processes contribute to both major depression and Alzheimer’s disease pathogenesis, it was only recently shown that Reelin expression is altered with inflammatory challenges and in several inflammatory conditions, including COVID-19. The observation that Reelin possesses antidepressant-like properties and inflammatory functions suggests Reelin dysregulation could potentially be important for inflammatory changes observed in these conditions. Although altered Reelin expression has been shown in disorders of inflammation, depression and Alzheimer’s disease, it is currently unknown whether administration of recombinant Reelin modifies inflammatory processes, or in other words, whether there exists a bidirectional relationship between Reelin expression and inflammatory processes. With this research, evidence is provided that exogenous Reelin administration can modulate inflammatory processes in stressed and non-stressed conditions.

Additionally, it has been shown that a blood-based biomarker for depression is modulated by Reelin signaling. Early findings related to this biomarker, membrane protein clustering of the serotonin transporter protein on peripherally circulating lymphocytes, show this biomarker can reliably differentiate depressed from non-depressed controls and within depressed populations, this biomarker can identify those that will respond to treatment and those that are likely to be resistant to antidepressant treatment effects. However, large-scale validation studies for this biomarker have yet to be conducted, in part due to the massive requirements for analyzing membrane protein clustering. This led to the development of an automated method for analyzing membrane protein clustering, which is described within this thesis.

Finally, while it is known that Reelin can modify membrane protein clustering and more neuropsychiatric conditions are marked by dysregulation of Reelin signaling than just major depression, there has yet to be an assessment of membrane protein clustering in many of these additional conditions (ex. epilepsy, multiple sclerosis, Alzheimer’s disease, etc.). This led to the evaluation of membrane protein clustering in a small sample of individuals diagnosed with mild cognitive impairment or Alzheimer’s disease. Results show relationships exist between membrane protein clustering characteristics and performance on tests of cognitive function as well as depressive symptoms. The results of membrane protein clustering in mild cognitive impairment and Alzheimer’s disease warrants further evaluation of membrane protein clustering in disorders marked by dysregulation of Reelin signaling.